Mutations

PSEN1 V89L (G>C)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73637682 G>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTG to CTG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation was identified in a patient with early onset, pathologically confirmed Alzheimer’s disease (Liu et al., 2017). Symptoms began at age 39 with memory difficulties. Neuropsychological testing at age 40 revealed deficits in memory, abstraction, and problem-solving. MRI did not show brain atrophy at this time, but FDG-PET showed hypometabolism in temporal and parietal lobes. Cognitive function continued to deteriorate, and the patient died at age 49. There was no clear family history of dementia.

This mutation not found in the 1000 Genomes, Exome Variant Server, ExAC, or AD&FTD databases. A PSEN1 V89L mutation due to a different nucleotide transversion was previously identified in a Spanish family with early onset AD (Queralt et al., 2002).

Neuropathology

At autopsy, typical AD pathology was observed, along with cerebral amyloid angiopathy. Amyloid plaque pathology was assessed as Thal phase 4, and neurofibrillary tangle pathology as Braak stage VI.  Atrophy and gliosis were widespread, including neocortical areas, medial temporal structures, and thalamus. No Lewy bodies were observed.

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant (nucleotide change unspecified) to cleave the APP-C99 substrate revealed it produces less Aβ42, and even less Aβ40, than wild-type PSEN1, resulting in an elevated Aβ42/Aβ40 ratio (Sun et al., 2017). Moreover, the mutation was predicted to be deleterious by SIFT and probably damaging by PolyPhen-2.

Last Updated: 27 Aug 2019

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References

Paper Citations

  1. . Two Novel Mutations in the First Transmembrane Domain of Presenilin1 Cause Young-Onset Alzheimer's Disease. J Alzheimers Dis. 2017;58(4):1035-1041. PubMed.
  2. . A novel mutation (V89L) in the presenilin 1 gene in a family with early onset Alzheimer's disease and marked behavioural disturbances. J Neurol Neurosurg Psychiatry. 2002 Feb;72(2):266-9. PubMed.
  3. . Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.

Other Citations

  1. PSEN1 V89L

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Two Novel Mutations in the First Transmembrane Domain of Presenilin1 Cause Young-Onset Alzheimer's Disease. J Alzheimers Dis. 2017;58(4):1035-1041. PubMed.

Other mutations at this position

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